Mol Divers DOI 10.1007/s11030-015-9607-1

FULL-LENGTH PAPER

Stereoselective chlorothiolation of artemisinin-derived C-10 oxa terminal alkynes Naresh Surineni1 · Pori Buragohain1 · Nabin C. Barua1

Received: 15 December 2014 / Accepted: 9 June 2015 © Springer International Publishing Switzerland 2015

Abstract A mild and efficient strategy is explored on the highly sensitive artemisinin-derived C-10 oxa terminal alkynes. Several novel artemisinin-derived (E)-2-chloroalkenyl sulfides (20) have been synthesized by using this protocol to study their anticancer activities. Keywords Artemisinin · Chlorothiolation · Alkynes · Vinyl sulfides

Introduction Artemisinin is the first natural endoperoxide containing unique sesquiterpene lactone isolated from the Chinese medicinal plant Artemisia annua [1]. Its first-generation derivatives, such as dihydroartemisinin (DHA), artemether, arteether, and sodium artesunate (Fig. 1), are used as firstline treatment for chloroquine-resistant and chloroquinesensitive malaria [2]. Recently, artemisinin and its derivatives have gained great attention as a new class of anticancer and antifungal agents [3]. A literature survey reveals that the trioxane ring system of artemisinin is mostly responsible for artemisinin’s outstanding antimalarial and anticancer activities [4,5]. In this context, it has been widely accepted that conditions or reagents used for derivatization of artemisinin must be carefully selected to keep the trioxane ring system Electronic supplementary material The online version of this article (doi:10.1007/s11030-015-9607-1) contains supplementary material, which is available to authorized users.

B 1

Nabin C. Barua [email protected] Natural Products Chemistry Division, CSIR-North East Institute of Science and Technology, Jorhat 785006, Assam, India

intact (Fig. 2). Efforts in this direction have yielded a large number of artemisinin analogs with profound anticancer or antimalarial activities, and are in different stages of clinical development [6–12,26]. In recent years, molecules containing vinyl sulfide moiety have emerged as a class of versatile organic small molecules that play an important role in organic chemistry, such as intermediates in the synthesis of small- and medium-sized rings like oxetanes [13], cyclopentanones [14], and cyclopentanes [15,16]. Many natural products and synthetic compounds containing the vinyl sulfide moiety exhibit promising biological properties, such as anticancer, antimalarial, antimicrobial, and antifungal activities [17–21]. In continuation of our interest in the synthesis of artemisinin derivatives as antimalarial and anticancer agents, we decided to introduce the vinyl sulfide moiety in the artemisnin framework to enhance its anticancer activity profile. Chlorothiolation is a straight forward reaction widely used in the synthesis of vinyl sulfides [22]. The simplest way to synthesize these products is via the addition of alkynes with aryl/alkyl sulfenylchlorides at room temperature [22]. In the chlorothiolation of alkynes, the regio/stereoselectivity can be achieved by varying the substrate alkyne and the catalyst used [23–25]. Accordingly, conventional methods show that the reactions of terminal alkynes with sulfenyl chloride proceed in an antifashion to give (E) adduct as the sole product [23]. Recently, Nishihara and coworkers [24] reported the highly regioselective and stereoselective addition of sulfenyl chloride to terminal alkynes using palladium catalysis to yield (Z )-2-chloroalkenyl sulfides with high efficiency, and iron catalysis to yield (E)-2-chloroalkenyl sulfides [25]. More importantly, Lee et al. reported the introduction of a sulfur atom to the artemisinin moiety affording new derivatives with unique biological properties that selectively control tumor-related angiogenesis [26]. Also, Oh et al. extended

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Mol Divers Fig. 1 Artemisinin and its clinically used derivatives

H 15 5

4 14

H

O2 1 O O 12

3

5a 12a

Fig. 2 Studies on sulphur containing artemisinin derivatives

10

8 8a

13

O 11

7

9

H

H

H

H

6

O O O

O O O

O O O

H

O

H

O

OH

1, Artemisinin

2, DHA

H

N

O

Lee's Study artemisinin

O

1

S

O

5, Artemisone

4, Sodium Artesunate

3, Artemether

Haynes' study

O O

H OCO(CH2)2COONa

OMe

H

O

O

16

O

O O O

H O O O O

O

SR

N Our study

R = H, phenyl, p-methoxyphenyl

S O O Artemisone

H O O O O O Cl

n

SR

R = Aryl, heteroaryl, alkyl

the synthesis of C-10 sulfone derivatives of artemisinin to produce C-10 exo olefinated deoxoartemisinin derivatives which displayed potent growth inhibitory activity when compared to artemisinin [27]. Moreover, Haynes et al. reported artemisone as one of the sulfur-containing second-generation derivatives of artemisinin which is now undergoing clinical trials [12]. Inspired by the potent anticancer sulfur-containing artemisinin derivatives, and in continuation of our interest in maximizing the structural diversity of artemisinin analogs to find potent anticancer agents, we wish to report the stereoselective chlorothiolation of artemisinin-derived C-10 oxa alkynes [6–11].

Results and discussion The artemisinin-derived C-10 oxa terminal alkynes 5a and 5b were initially prepared from artemisinin as shown in Scheme 1. Accordingly, artemisinin is treated with NaBH4 in MeOH at 0 ◦ C to afford dihydroartemisinin 2 in 90 % yield which upon treatment with propargyl/homopropargyl alcohol in the presence of BF3 ·OEt2 in dichloromethane afforded artemisinin-derived terminal alkynes 5a/5b [6– 11]. Initially, we attempted the chlorothiolation reaction on 5a in dichloroethane using 4-methylbenzenesulfenylchloride

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which was generated in situ from the reaction of 4-methylbenzenthiol with N-chlorosuccinamide [28]. The reaction underwent smoothly to completion in 5 h (monitored by TLC) to give product 6a in 52 % isolated yield. Interestingly, we observed that product 6a was obtained as an E-isomer with high regio- and stereoselectivity as confirmed by 1 H NMR, 13 C NMR, Mass Spectrum, and NOSEY analysis. NOSEY of 6a recorded NOE coupling interactions between the H9 and H10 protons of artemisinin and the Ha proton of the phenyl group, confirming the E-isomer configuration of the product (Fig. 3). In order to optimize the reaction conditions, we also used acetonitrile and toluene at different temperatures up to 70 ◦ C and found that no desired products were formed. However, when the solvent was changed to dichloromethane, the reaction was complete in 2 h affording the desired chlorothiolated adduct 6a with 73 % yield. We used this reaction system with a wide array of diverse aryl thiols, alkyl thiols, and heteroaryl thiols for the synthesis of 6b to 6t (Table 1). The addition of various sulfenyl chlorides was very fast and afforded the desired products in excellent yields tolerating a variety of functional groups, such as –F, –Br, –Cl, –Me, and –OMe. The addition of hetero arylsulfenyl chlorides was slow compared to arylsulfenyl chlorides. To our surprise, when heteroaryl sulfenyl chlorides prepared from 2-pyrimidyl thiol

Mol Divers Scheme 1 General reaction sequence for the artemisinin-derived chlorothiolation adducts

and 2-mercaptobenzothiazole were reacted with the alkyne 5a, the reactions did proceed to afford their corresponding (E)-2-chloroalkenyl sulfides and instead of the desired products, we isolated dihydrartemisinin as a side product in both experiments. In the above cases, heteroaryl sulfenyl chlorides might facilitate the hydrolysis of alkyne 5a rather than undergo chlorothiolation. To further extend the utility of our protocol, we performed the oxidation reaction of sulfide 6k to its corresponding sulfone derivative 7 using excess m-CPBA (Scheme 2). In this reaction, no traces of the sulfoxide intermediate were detected.

Conclusion Fig. 3 Representative NOESY diagram of 6a

Table 1 Chlorothiolated adducts of artemisinin-derived C-10 oxa terminal alkynes

In conclusion, we have developed a convenient, simple, stereoselective chlorothiolation of artemisinin-derived C-10 oxa terminal alkynes under metal-free conditions. Studies

Entry

R

Alkyne

Product

Time (h)

% Yielda

1

4-MeC6 H4

5a

6a

2

73

2

4-BrC6 H4

5a

6b

2.5

78

3

4-ClC6 H4

5a

6c

3

74

4

4-MeC6 H4

5b

6d

3

70.8

5

4-BrC6 H4

5b

6e

2.5

72.8

6

4-ClC6 H4

5b

6f

3

75.8

7

2-ClC6 H4

5a

6g

3

65.6

8

2-MeC6 H4

5a

6h

2

70

9

1-Phenyl-1H-tetraazolyl

5b

6i

4

52.8

10

2-ClC6 H4

5b

6j

3

63.8

11

2-MeC6 H4

5b

6k

3

64.5

12

2-Benzothiazolyl

5b

6l

4

53.8

13

2-Pyrimidyl

5b

6m

5

50.8

14

4-MeOC6 H4

5b

6n

3

67.8

15

4-FC6 H4

5b

6o

3.5

69.8

16

4-MeOC6 H4

5a

6p

3

68.8

17

Cyclohexyl

5a

6q

2

69.8

18

Cyclohexyl

5b

6r

2

52.8

19

2-MeOC6 H4

5a

6s

3

60.8

20

2-MeOC6 H4

5b

6t

3

60.2

a

Isolated yields after column chromatography

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Mol Divers Scheme 2 Oxidation transformation of 6k into sulfone 7

on detailed bio-evaluation of artemisinin-derived chlorothiolated compounds are currently under progress.

moiety has been named as artemisinyl in the following named products).

Experimental section

(E)-2-Chloro-artemisinyl propenyl 4-methyl phenyl sulfide (6a)

All the glass equipment was oven dried prior to use. Infrared spectra were recorded on a Perkin–Elmer 1640 FT-IR spectrometer. 1 H NMR, 13 C NMR spectra were recorded on a Bruker DPX 300 MHz, 75 MHz, and 500 MHz, 125 MHz using CDCl3 as the deuterated solvent and internal reference [7.26 ppm (1 H); 77.10 ppm (13 C)]. All the spectral data are reported in chemical shifts (ppm), multiplicity (s for singlet, d for doublet, t for triplet, m for multiplet, br broad signal), and coupling constant(s) (Hz). Mass spectra were recorded on a Bruker Daltonic Data Analyser 2.0 spectrometer. All the synthesized compounds were purified by using flash column chromatography using Rankem silica gel 100–200 mesh size. Preparative TLC was performed using aluminum precoated TLC silica gel 60 F254 plates. All the reactions were performed using anhydrous solvents. Moisture-sensitive reactions were conducted under a dry argon atmosphere. CH3 CN, CH2 Cl2 was dried over P2 O5 , and toluene was dried over sodium. All the solvents were distilled at their boiling points and other commercially available chemicals used as received, unless otherwise stated. General procedure for the synthesis of chlorothiolated artemsinin derivatives To a solution of aryl/heteroaryl thiols (0.55 mmol) in CH2 Cl2 (4 mL) was added N -chlorosuccinimde (0.55 mmol), and the reaction mixture was allowed to be stirred for 5 minutes to form sulfenylchlorides as yellow-colored solution. To this stirred solution of sulfenylchloride was added alkyne 5a/5b (0.5 mmol), and the reaction mixture was again stirred for 2–5 h. After completion of the reaction (monitored by TLC), water (10 mL) was added to the reaction mixture, and extraction was performed with CH2 Cl2 (3 × 10 mL). The combined organic layers were washed with brine (10 mL) and dried over anh. sodium sulfate. The organic layer was concentrated using a rotary evaporator and chromatographed on silica gel (100–200 mesh) using 1:9 ethyl acetate–hexane as the eluent to give pure (E)-2-chloroalkenyl sulfides (the artemisinin

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Gummy liquid, yield: 73 %. 1 H NMR (300 MHz, CDCl3 ) δ: 7.30 (d, J = 8.1 Hz, 2H), 7.13 (d, J = 7.8 Hz, 2H), 6.1 (s, 1H), 5.38 (s, 1H), 4.78 (d, J = 2.34, 1H), 4.72 (d, J = 12.8 Hz, 1H), 4.52 (d, J = 12 Hz, 1H), 1.19–2.63 (m, 12H, aliphatic region), 2.33 (s, 3H),1 .42 (s, 3H), 0.95 (d, J = 8.3Hz, 3H), 0.89 (d, J = 7.7 Hz, 3H) . 13 C NMR (75MHz, CDCl3 ) δ: 137.9, 135.6, 131.9, 130.0, 119.2, 104.4, 102.2, 88.0, 81.1, 65.4, 52.5, 44.4, 37.3, 36.4, 34.6, 30.9, 26.1, 24.6, 24.2, 21.1, 20.3, 12.9. IR (CHCl3 )ν: 2922, 1475, 1100, 1012 cm−1 MS (ESI) m/z: calcd: 480.17, found: (M+ ) 480.10 (E)-2-Chloro-3-artemisinyl propenyl 4-bromo phenyl sulfide (6b) Gummy liquid, yield: 78.1 %. 1 H NMR (300 MHz, CDCl3 ) δ: 7.28 (s, 4H, br), 6.38 (s, 1H), 5.34 (s, 1H), 4.68 (d, J = 3.1 Hz , 1H), 4.59 (d, J = 12.2 Hz, 1H), 4.25 (d, J = 12.3 Hz , 1H), 2.60–2.62 (m, 2H), 1.21–2.32 (m, 10H, aliphatic region), 1.42 (s, 3H), 0.95 (d, J = 4.3 Hz, 3H), 0.86 (d, J = 7.3 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ: 134.1, 133.5, 132.1, 131.8, 129.3, 122.4, 104.0, 102.3, 88.0, 81.0, 65.6, 52.5, 44.3, 37.3, 36.4, 34.6, 30.9, 26.1, 24.6, 24.2, 20.3, 12.9. IR (CHCl3 ) ν: 2923, 1475, 1101, 1013 cm−1 ; MS (ESI) m/z: calcd: 544.07, found: (M+ ) 544.42. (E)-2-Chloro-3-artemisinyl propenyl 4-chloro phenyl sulfide (6c) Light yellow gummy liquid, yield: 74 %. 1 H NMR (300 MHz, CDCl3 ) δ: 7.28 (s, 4H, br), 6.38 (s, 1H), 5.34 (s, 1H), 4.78 (d, J = 2.9 Hz, 1H), 4.59 (d, J = 12.4 Hz, 1H), 4.25 (d, J = 11.1 Hz, 1H), 1.19–2.63 (m, 12H, aliphatic region), 1.42 (s, 3H), 0.95 (d, J = 4.9 Hz, 3H), 0.88 (d, J = 7.3 Hz, 3H). 13 C NMR (75MHz, CDCl ) δ: 134.1, 133.5, 132.1, 131.8, 3 129.3, 122.4, 104.0, 102.3, 88.0, 81.0, 65.6, 52.5, 44.3, 37.3, 36.4, 34.6, 30.9, 26.1, 24.6, 24.2, 20.3, 12.9. IR (CHCl3 ) ν:

Mol Divers

2922, 1475, 1100, 1012 cm−1 MS (ESI) m/z: calcd: 500.12, found: (M+ ) 500.42. (E)-2-Chloro-4-artemisinyl butenyl 4-methyl phenyl sulfide (6d) Gummy liquid, yield: 70.8 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.33 (m, 2H), 7.11 (m, 2H), 6.24 (s, 1H), 5.42 (s, 1H), 4.77 (d, J = 5.1 Hz, 1H), 4.07 (m, 1H), 3.53 (m, 1H), 2.58 (m, 2H), 1.21–2.36 (m, 12H, aliphatic region), 2.33 (s, 3H), 1.44 (s, 3H), 0.94 (d, J = 5.8 Hz, 3H), 0.88 (d, J = 7.5 Hz, 3H). 13 C NMR (75MHz, CDCl ) δ: 137.9, 135.7, 131.8, 130.0, 3 129.0, 118.8, 104.2, 102.0, 87.9, 81.0, 65.2, 52.5, 44.3, 37.4, 34.6, 32.6, 30.9, 30.7, 26.2, 24.7, 24.3, 21.1, 20.3, 12.9. IR (CHCl3 )ν: 2922, 1475, 1100, 1012 cm−1 MS (ESI) m/z: calcd: 494.19 found: (M+ ) 494.12. (E)-2-Chloro-4-artemisinyl butenyl 4-bromo phenyl sulfide (6e) Gummy liquid, yield: 75.8 %.1 H NMR (300 MHz, CDCl3 δ: 7.30 (m, 4H), 6.40 (s, 1H), 5.42 (s, 1H), 4.78 (d, J = 5.1 Hz, 1H), 4.13 (m, 1H), 3.50 (m, 1H), 2.63 (m, 2H), 1.21–2.36 (m, 12H aliphatic region), 1.44 (s, 3H), 0.96 (d, J = 5.8 Hz, 3H), 0.87 (d, J = 7.5 Hz, 3H) . 13 C NMR (75MHz, CDCl3 ) δ: 139.5, 134.1, 133.1, 132.5, 129.6, 121.4, 104.1, 102.2, 87.9, 81.0, 65.0, 52.5, 44.3, 37.4, 34.6, 33.6, 30.8, 30.7, 26.1, 24.7, 24.3, 21.0, 12.9. IR (CHCl3 ) ν: 2922, 1475, 1100, 1012 cm−1 MS (ESI) m/z: calcd: 558.08, found: (M+ ) 558.42. (E)-2-Chloro-4-artemisinyl butenyl 4-chloro phenyl sulfide (6f) Gummy liquid, yield: 72.8 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.28 (m, 4H), 6.41 (s, 1H), 5.40 (s, 1H), 4.78 (d, J = 3.2 Hz, 1H), 3.98 (m, 1H), 3.52 (m, 1H), 2.59 (m, 2H) , 1.21– 2.37 (m, 12H, aliphatic region), 1.44 (s, 3H), 0.96 (d, J = 6 Hz, 3H), 0.90 (d, J = 7.3 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ: 134.5, 133.6, 132.1, 131.7, 130.5, 129.45, 121.4, 104.07, 102.01, 87.9, 81.1, 65.0, 52.5, 44.3, 37.4, 36.4, 34.6, 31.1, 30.8, 26.1, 24.7, 24.3, 21.0, 20.4, 12.9. IR (CHCl3 ) ν: 2923, 1475, 1101, 1013 cm−1 MS (ESI) m/z: calcd: 514.13, found: (M+ ) 514.46. (E)-2-Chloro-3-artemisinyl propenyl 2-chloro phenyl sulfide (6g) Gummy liquid, yield: 65.6 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.43 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 7.1 Hz, 1H), 7.09 (m, 2H), 6.45 (s, 1H), 5.28 (s, 1H), 4.73 (d, J = 2.3 Hz, 1H), 4.61 (d, J = 12.5 Hz, 1H), 4.24 (d, J = 12.1 Hz, 1H), 1.19–2.63 (m, 10H, aliphatic region), 1.34 (s, 3H), 0.85 (d, J = 2.7 Hz, 3H), 0.76 (d J = 7.3 Hz, 3H).13 C NMR

(75 MHz, CDCl3 ) δ: 134.2, 133.1, 131.2, 129.9, 127.6, 127.2, 124.9, 104.1, 102.2, 88.0, 81.0, 65.7, 52.5, 44.3, 37.4, 37.2, 34.6, 30.8, 26.1, 24.6, 24.0, 20.2, 14.2. IR (CHCl3 ) ν: 2922, 1450, 1101, 1031 cm−1 MS (ESI) m/z: calcd: 486.10, found: (M+ ) 486.42.

(E)-2-Chloro-3-artemisinyl propenyl 2-methyl phenyl sulfide (6h) Gummy liquid, yield: 68.8 %. 1 H NMR (300 MHz, CDCl3 ) δ: 7.32 (d, J = 7.17 Hz, 1H), 7.12 (m, 3H), 5.96 (s, 1H), 5.39 (s , 1H), 4.82 (d, J = 3.21 Hz, 1H), 4.61 (d, J = 12.24 Hz, 1H), 4.22 (d, J = 12.15 Hz, 1H), 1.19–2.63 (m, 10H, aliphatic region), 2.37 (s, 3H), 1.42 (s, 3H), 0.94 (d, J = 5.52 Hz, 3H), 0.88 (d, J = 7.3 Hz, 3H).13 C NMR (75MHz, CDCl3 ) δ: 139.6, 134.4, 132.4, 130.7, 128.1, 126.8, 118.3, 104.0, 102.1, 88.0, 81.1, 65.6, 52.5, 44.4, 37.4, 36.4, 34.5, 30.9, 26.1, 24.6, 24.0, 20.3, 20.2, 12.9. IR (CHCl3 ) ν: 2922, 1450, 1101, 1031cm−1 MS (ESI) m/z: calcd: 466.16 found: (M+ ) 466.02.

(E)-2-Chloro-4-artemisinyl butenyl 1-Phenyl-1H-tetrazolyl sulfide (6i) Gummy liquid, yield: 52.8 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.57 (d, J = 2.55 Hz, 5H), 6.81 (s, 1H), 5.39 (s, 1H), 4.73 (d, J = 2.61 Hz, 1H), 4.01 (m, 1H), 3.53 (m, 1H), 2.97 (t, J = 6.24 Hz, 2H), 1.15–2.36 (m, 12H, aliphatic region), 1.41 (s, 3H), 0.94 (d, J = 5.7 Hz, 3H), 0.85 (d, J = 7.3 Hz, 3H). 13 C NMR (75MHz, CDCl ) δ: 152.1, 133.5, 130.5, 129.9, 3 128.5, 124.1, 104.1, 102.0, 87.9, 81.0, 64.9, 52.4, 44.2, 37.4, 36.3, 34.5, 31.7, 30.9, 30.7, 26.1, 24.6, 24.3, 20.1, 12.9. IR (CHCl3 ) ν: 2924, 1561, 1381, 1103, 1022 cm−1 MS (ESI) m/z: calcd: 548.19 found: (M+ ) 548.10.

(E)-2-Chloro-4-artemisinyl propenyl 2-chloro phenyl sulfide (6j) Gummy, yield: 63.8 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.57 (d, J = 6.5 Hz, 1H), 7.16 (m, 3H), 6.49 (s, 1H), 5.44 (s, 1H), 4.79 (d, J = 2.8 Hz, 1H), 4.01 (m, 1H), 3.55 (m, 1H), 2.65 (m, 2H), 1.21-2.36 (m, 12H, aliphatic region), 1.44 (s, 3H), 0.94 (d, J = 5.8 Hz, 3H), 0.88 (d, J = 7.5 Hz, 3H). 13 C NMR (75MHz, CDCl3 ) δ: 134.5, 133.3, 132.8, 131.0, 130.1, 123.4, 104.0, 102.2, 88.0, 81.1, 65.2, 52.5, 44.3, 37.3, 36.4, 34.6, 31.5, 30.9, 26.1, 24.7, 24.3, 21.0, 12.9. IR (CHCl3 ) ν: 2922, 1475, 1100, 1012 cm−1 MS (ESI) m/z: calcd: 514.13, found: (M+ ) 514.02.

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Mol Divers

(E)-2-Chloro-4-artemisinyl propenyl 2-methyl phenyl sulfide (6k) Gummy, yield: 64.5 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.32 (d, J = 7.16 Hz, 1H), 7.16 (m, 3H), 6.05 (s, 1H), 5.40 (s, 1H), 4.80 (d, J = 3.03 Hz, 1H), 4.01–4.04 (m, 1H), 3.53– 3.56 (m, 1H), 2.60 (t, J = 6.33 Hz, 2H), 1.21–2.36 (m, 12H, aliphatic region), 2.39 (s, 3H), 1.44 (s, 3H), 0.94 (d, J = 6.15 Hz, 3H), 0.89 (d, J = 7.35 Hz, 3H). 13 C NMR(75MHz, CDCl3 ) δ: 139.9, 134.7, 132.3, 131.5, 130.7, 128.1, 126.7, 117.8, 104.0, 102.1, 87.9, 81.1, 65.4, 52.6, 44.4, 37.4, 34.6, 31.5, 30.9, 26.2, 24.7, 24.3, 20.4, 20.3 12.9. IR (CHCl3 ) ν: 2922, 1475, 1100, 1012 cm−1 MS (ESI) m/z: calcd: 494.19, found: (M+ ) 494.05. (E)-2-Chloro-4-artemisinyl butenyl 2-benzothiazolyl sulfide (6l) Gummy, yield: 53.8 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.90 (d, J = 8.1 Hz, 1H), 7.76 (d, J = 7.92 Hz, 1H), 7.42 (t, J = 7.41 Hz, 1H), 7.31 (t, J = 7.53 Hz, 1H), 6.98 (s,1H), 5.39 (s, 1H), 4.79 (d, J = 2.82 Hz, 1H), 4.08 (m, 1H), 3.62 (m, 1H), 2.93 (t, J = 6.12 Hz, 2H), 1.15–2.36 (m, 12H, aliphatic region), 1.43 (s, 3H), 0.93 (d, J = 5.94 Hz, 3H), 0.87 (d, J = 7.26 Hz, 3H). 13 C NMR (75MHz, CDCl3 ) δ: 152.5, 135.7, 131.7, 128.7, 126.4, 124.8, 122.2, 121.0, 104.1, 102.0, 87.9, 81.0, 65.0, 52.5, 44.3, 37.4, 36.4, 34.6, 32.2, 30.8, 30.7, 26.1, 24.6, 24.3, 20.4, 12.9. IR (CHCl3 ) ν: 2952, 1461, 1103, 1022 cm−1 MS (ESI) m/z: calcd: 537.14, found: (M+ ) 537.12.

116.6, 114.8, 103.9, 101.9, 87.8, 81.01, 65.1, 55.2, 52.4, 47.9, 44.2, 37.3, 36.6, 34.5, 32.5, 30.8, 29.6, 26.1 , 24.5, 24.4, 20.3, 12.8. IR (CHCl3 ) ν: 2923, 1560, 1371, 1025 cm−1 MS (ESI) m/z: calcd: 510.18, found: (M+ ) 510.12. (E)-2-Chloro-4-artemisinyl butenyl 4-fluoro phenyl sulfide (6o) Gummy, yield: 69.8 %.1 H NMR (500 MHz, CDCl3 ) δ: 7.29 (m, 2H), 6.92 (m, 2H), 6.29 (s, 1H), 5.41 (s, 1H), 4.79 (d, J = 3.6 Hz, 1H), 4.02 (m, 1H), 3.53 (m, 1H), 1.22–2.65 (m, 14H, aliphatic region), 1.45 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 7.5Hz, 3H). 13 C NMR (100MHz, CDCl3 ) δ: 163.4, 161.4, 135.3, 133.7, 127.6, 119.5, 116.3, 103.9, 101.9, 87.8, 81.0, 65.0, 52.4, 44.2, 37.3, 36.3, 34.5, 30.7, 26.1, 24.5, 24.2, 20.3, 12.8. IR (CHCl3 ) ν: 2925, 1565, 1380, 1022 cm−1 MS (ESI) m/z: calcd: 498.18, found: (M+ ) 498.19. (E)-2-Chloro-3-artemisinyl propenyl 4-methoxy phenyl sulfide (6p) Gummy, yield: 68.8 %.1 H NMR (300 MHz, CDCl3 ) δ: 7.29 (m, 2H), 6.75 (m, 2H), 5.94 (s, 1H), 5.42 (s, 1H), 4.80 (d, J = 3.0 Hz, 1H), 4.53 (d, J = 12.5 Hz, 1H), 4.20 (d, J = 12.0 Hz, 1H), 3.80 (s, 3H), 1.21–2.36 (m, 12H, aliphatic region), 1.44 (s, 3H), 0.94 (d, J = 6.5 Hz, 3H), 0.89 (d, J = 7.5 Hz, 3H). 13 C NMR (75 MHz, CDCl3 ) δ: 159.9, 136.7, 134.8, 122.0, 116.6, 114.8, 103.95, 102.0, 87.9, 81.0, 65.2, 55.2, 52.4, 44.2, 37.2, 36.2, 34.5, 30.8, 26.0, 24.5, 24.1, 20.2, 12.9. IR (CHCl3 ) ν: 2925, 1560, 1361, 1026 cm−1 MS (ESI) m/z: calcd: 496.16, found: (M+ ) 496.12.

(E)-2-Chloro-4-artemisinyl butenyl 2-pyrimidyl sulfide (6m) (E)-2-Chloro-3-artemisinyl propenyl cyclohexyl sulfide (6q) Gummy, yield: 50.8 %.1 H NMR (300 MHz, CDCl3 ) δ: 8.53 (d, J = 4.7 Hz, 2H), 7.00 (t, J = 4.8 Hz, 1H), 6.75 (s, 1H), 5.44 (s, 1H), 4.78 (d, J = 3.09 Hz, 1H), 4.74 (m, 1H), 3.63 (m, 1H), 1.21–2.36 (m, 14H, aliphatic region), 1.42 (s, 3H), 0.94 (d, J = 6.06 Hz, 3H), 0.89 (d, J = 7.3 Hz, 3H). 13 C NMR (75MHz, CDCl ) δ: 171.6, 157.5, 131.4, 126.5, 3 117.19, 104.1, 101.1, 87.8, 81.01, 65.03, 52.4, 44.2, 37.2, 36.3, 34.5, 32.5, 31.1, 30.7, 26.06, 24.5, 24.3, 20.3, 12.8. IR (CHCl3 ) ν: 2924, 1561, 1381, 1022 cm−1 MS (ESI) m/z: calcd: 482.16, found: (M+ ) 482.42.

Gummy, yield: 69.8 %.1 H NMR (500 MHz, CDCl3 ) δ: 6.34 (s, 1H), 5.53 (s, 1H), 4.88 (d, J = 3.5 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 3.63 (d, J = 11.5 Hz, 1H), 1.21–2.36 (m, 12H, aliphatic region), 1.45 (s, 3H), 0.94 (d, J = 5.5 Hz, 3H), 0.89 (d, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3 ) δ: 133.3, 120.5, 103.9, 101.9, 88.0, 81.0, 66.39, 5.4, 44.3, 44.1, 37.3, 36.3, 34.58, 33.0, 32.8, 30.8, 26.0, 25.8, 25.7, 25.5, 24.5, 24.2, 20.2, 12.9. IR (CHCl3 ) ν: 2920, 1551, 1371, 1012 cm−1 MS (ESI) m/z: calcd: 472.21, found: (M+ ) 472.01.

(E)-2-Chloro-4-artemisinyl butenyl 4-methoxy phenyl sulfide (6n)

(E)-2-Chloro-4-artemisinyl butenyl cyclohexyl sulfide (6r)

Gummy, yield: 67.8 %.1 H NMR (500 MHz, CDCl3 ) δ: 7.37 (d, J = 4.8 Hz, 2H), 7.02 (d, J = 4.8 Hz, 2H), 6.10 (s, 1H), 5.45 (s, 1H), 4.81 (d, J = 3.5 Hz, 1H), 4.06 (m ,1H), 3.79 (s, 3H), 3.53 (m, 1H), 1.21–2.36 (m, 14H, aliphatic region), 1.47 (s, 3H), 0.94 (d, J = 7.2 Hz, 3H), 0.89 (d, J = 4.5, 3H). 13 C NMR (100 MHz, CDCl ) δ: 159.8, 136.6, 134.4, 122.3, 3

Gummy, yield: 52.8 %.1 H NMR (500 MHz, CDCl3 ) δ: 6.21 (s, 1H), 5.43 (s, 1H), 4.78 (d, J = 3.5 Hz, 1H), 4.04 (m, 1H), 3.58 (m, 1H), 1.15–2.36 (m, 25H, aliphatic region), 1.44 (s, 3H), 0.94 (d, J = 7.0 Hz, 3H), 0.88 (d, J = 7.5 Hz, 3H). 13 C NMR (100 MHz, CDCl ) δ: 133.9, 117.8, 103.9, 101.8, 3 87.8, 81.0, 65.3, 52.4, 44.2, 43.9, 37.2, 36.3, 34.5, 33.0, 32.9,

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Mol Divers

32.0, 30.8, 26.7, 25.7, 25.58, 24.5, 24.1, 20.3, 19.9, 12.8. IR (CHCl3 ) ν: 2914, 1531, 1361, 1022 cm−1 MS (ESI) m/z: calcd: 486.22, found: (M+ ) 486.15. (E)-2-Chloro-3-artemisinyl propenyl 2-methoxy phenyl sulfide (6s) Gummy, yield: 60.8 %.1 H NMR (500 MHz, CDCl3 ) δ: 7.23 (m, 2H), 6.85 (m, 2H), 6.30 (s, 1H), 5.41 (s, 1H), 4.81 (d, J = 3.0 Hz, 1H), 4.63 (d, J = 12.5 Hz, 1H), 4.22 (d, J = 12.0 Hz, 1H), 3.85 (s, 3H), 1.20–2.61 (m, 12H, aliphatic region), 1.41 (s, 3H), 0.92 (d, J = 6.0 Hz, 3H), 0.88 (d, J = 7.0 Hz, 3H). 13 C NMR (100 MHz, CDCl3 ) δ: 157.1, 133.0, 131.2, 128.5, 121.9, 121.1, 110.7, 103.9, 102.0, 87.9, 81.0, 65.8, 55.7, 52.4, 44.2, 37.1, 36.2, 34.6, 30.8, 26.0, 24.5, 24.0, 20.2, 12.8. IR (CHCl3 ) ν: 2925, 1561, 1371, 1012 cm−1 MS (ESI) m/z: calcd: 496.17, found: (M+ ) 496.10. (E)-2-Chloro-4-artemisinyl propenyl 2-methoxy phenyl sulfide (6t) Gummy, yield: 60.2 %.1 H NMR (500 MHz, CDCl3 ) δ: 7.21 (m, 2H), 6.87 (m, J = 4.8 Hz, 1H), 6.31 (s, 1H), 5.44 (s, 1H), 4.78 (d, J = 3.0 Hz, 1H), 3.99 (m, 1H), 3.87 (s, 3H), 3.53 (m, 1H), 1.19–2.70 (m, 14H, aliphatic region), 1.44 (s, 3H), 0.94 (d, J = 6.0 Hz, 3H), 0.89 (d, J = 7.5 Hz, 3H). 13 C NMR (100MHz, CDCl ) δ: 157.6, 133.5, 131.5, 128.7, 3 121.1, 120.3, 110.9, 103.9, 101.8, 87.8, 81.0, 65.2, 55.7, 52.4, 44.3, 37.2, 36.3, 34.5, 31.4, 30.8, 26.1, 24.5, 24.2, 20.3, 12.8. IR (CHCl3 ) ν: 2924, 1561, 1381, 1022 cm−1 MS (ESI) m/z: calcd: 510.18, found: (M+ ) 510.12. (E)-2-Chloro-4-artemisinyl butenyl 4-methyl phenyl sulfone (7) Gummy liquid, yield : 80 % 1 H NMR (300 MHz, CDCl3 ) δ: 8.09 (d, J = 7.8 Hz, 1H), 7.57 (t, J = 7.83 Hz, 1H), 7.53 (s, 1H), 7.43 (t, J = 7.62 Hz, 1H), 7.33 (d, J = 7.5 Hz, 1H), 5.30 (s, 1H), 4.59 (d, J = 3.18 Hz, 1H), 3.80 (m, 1H), 3.21 (m, 1H), 2.66 (m, 2H), 1.21–2.36 (m, 12H, aliphatic region), 2.54 (s, 3H), 1.42 (s, 3H), 0.94 (d, J = 6.15 Hz, 3H), 0.88 (d, J = 7.35 Hz, 3H). 13 C NMR (75MHz, CDCl3 ) δ: 140.8, 138.4, 135.8, 134.3, 133.9, 133.0, 130.6, 126.8, 104.0, 102.1, 87.8, 64.9, 52.5, 44.3, 37.3, 36.4, 34.6, 30.7, 27.6, 26.1, 24.6, 24.3, 20.3, 20.1, 12.9. IR (CHCl3 ) ν: 2924, 1455, 1317, 1155, 1022 cm−1 MS (ESI) m/z: calcd: 526.18, found (M+ ) 526.42. Acknowledgments The authors would like to thank the Director, CSIR-NEIST, Jorhat, for providing necessary facilities to carry out artemisinin work. N.S. thanks UGC, P.B. thanks CSIR for the grant of research fellowships, and thanks are also due to P.J. Saikia for NOESY spectral characterization, Analytical Chemistry division of CSIR-NEIST.

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Stereoselective chlorothiolation of artemisinin-derived C-10 oxa terminal alkynes.

A mild and efficient strategy is explored on the highly sensitive artemisinin-derived C-10 oxa terminal alkynes. Several novel artemisinin-derived (E)...
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